Glycogen synthase kinase-3beta (GSK3beta) inhibition suppresses the inflammatory response to Francisella infection and protects against tularemia in mice.
Francisella tularensis, the causative agent of tularemia, is currently considered a category A bioterrorism agent due to its high virulence. Infection with F. tularensis results in an inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms regulating this response are poorly understood. Glycogen synthase kinase-3beta (GSK3beta) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. In this study, we investigated the effect of GSK3beta inhibition in regulating F. tularensis LVS-induced inflammatory responses. F. tularensis LVS infection of murine peritoneal macrophages induced a TLR2 dependent phosphorylation of GSK3beta. Inhibition of GSK3beta resulted in a significant decrease in the production of pro-inflammatory cytokine IL-6, IL-12p40 and TNF-alpha, as well as a significant increase in the production of the anti-inflammatory cytokine IL-10. GSK3beta regulated the F. tularensis LVS-induced cytokine response by differentially affecting the activation of transcription factors NF-kappaB and CREB. Inhibition of GSK3beta by lithium in vivo suppressed the inflammatory response in mice infected with F. tularensis LVS and conferred a survival advantage. In addition, we show that the production of IFN-gamma contributed to the development of tularemia and to the fatal outcome of the infected animals, depending on the timing and the relative level of the IFN-gamma produced. IFN-gamma potentiated F. tularensis LVS-induced cytokine production by increasing GSK3beta activity and the nuclear translocation of NF-kappaB. Taken together, these results demonstrate a regulatory function of GSK3beta in modulating inflammatory responses that can be detrimental to the host during an F. tularensis LVS infection, and suggest that inhibition of GSK3beta may represent a novel therapeutic approach in the treatment of tularemia.
Zhang
Ping
P
Department of Pediatric Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Katz
Jenny
J
Michalek
Suzanne M
SM
D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005604:Francisella tularensis; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D018021:Lithium Chloride / Q000627:therapeutic use; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D014406:Tularemia / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride